Affiliation:
1. Roche Pharma Research & Early Development (pRED), Pharmaceutical Sciences, Bioanalysis & Biomarkers, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, Penzberg, 82377, Germany
Abstract
Analysis of “free” drug/target concentrations is important to set up appropriate pharmacokinetic–pharmacodynamic models, to evaluate active-drug exposure and target engagement. Such “free-analyte” determination could be done by direct bioanalysis using an appropriate “free-analyte” assay. Development of “free” assays is often considered challenging from a technological and regulatory perspective. The application of a “total-total” approach, where the “free-analyte” concentration is determined mathematically, is considered a more convenient option. In this perspective, we examine and discuss the challenges of this “total-total” approach, from the affinity data, the importance of applying an appropriate “total” assay, the impact of additional binding partners and the variability of the total drug/target assays and their impact on the quality and variability of the final “free-analyte” dataset.
Subject
Medical Laboratory Technology,Clinical Biochemistry,General Pharmacology, Toxicology and Pharmaceutics,General Medicine,Analytical Chemistry